The long term objective of this project is to generate novel cytotoxic agents that inhibit cancer cell proliferation. Epothilone D, a 16-membered polyketide-derived macrolactone, has promising activity but is produced in low titers by the native organism, Sorangium cellulosum, and is only sparingly soluble in water. Chemical synthesis of epothilones has been achieved but the methods are elaborate and costly. Recently, Kosan has developed fermentation processes for the heterologous production of Epothilone D in large quantities. The ready availability of this compound offers a unique opportunity for partial chemical synthesis of new analogs. In Phase I, chemical methods will be used to generate a number of analogs of Epothilone D and the analogs will be tested for potency and water solubility. The most promising candidate(s) which are at least as potent as, and more water soluble than the parent will be carried forward into Phase II to develop commercially feasible production methods. PROPOSED COMMERCIAL APPLICATION: Epothilone is widely acclaimed as a successor to paclitaxel (TaxolTM) and is more effective against multiple drug resistant tumors. The proposed epothilone analogs with increased solubility will have a potentially competitive advantage for a $2 billion per year market for the treatment of breast, lung and ovarian cancers.